Project Summary The long term goal of this research program is to identify epigenetic mechanisms involved in sex differences in neurobehavioral diseases. Basic research on sex differences in behavior reveals two mechanisms. The best documented is differences in circulating levels of gonadal hormones in male versus female embryos and neonates which shape neuronal cell migration, connections and structures and are responsible for many adult behaviors. In addition, sex chromosome genes themselves are correlated with a number of sexually dimorphic behaviors. This latter mechanism has parallels in humans in which X-chromosome genes are linked to many mental disorders. Here we will ask whether the endocrine disrupting compound, bisphenol A (BPA), can modify behavior and if so whether it acts as a hypomethylator on candidate X-chromosome genes. In Aim 1 we will examine independent effects of sex chromosome and gonadal sex, in conjunction with BPA, on juvenile social behavior in mice. In Aim 2 we will conduct gene expression arrays to validate a set of candidate genes affected by BPA exposure during neural development. In the final aim we will ask if DNA methylation status in candidate gene promoters is affected by BPA and if histone methylation is likewise affected. We will use genetically engineered mice, molecular, genetic and behavioral methods to reveal epigenetic interactions between sex chromosome genes and BPA. The goal of our research is to find genes and processes that can help diagnose, treat and prevent mental illnesses. Understanding the epigenetic, as well as the genetic, bases for neurobehavioral diseases is essential for diagnosis, prevention and treatment. Here we focus on one environmental factor, bisphenol A, a man-made chemical that has the capacity to affect gene transcription through several mechanisms, and to which exposure during development may affect brain organization. Given the large sex differences in the prevalence of several neurobehavioral diseases (for example, autism is found 4 times more often in boys than in girls), we focus on epigenetic modification of mechanisms that underlie sex differences in behavior.